Macrovascular Complications of Diabetes

Macrovascular Complications of Diabetes - 1.Cardiovascular Disease
2.Cereberovascular Accident
3.Peripheral Vascular Disease

1. MACROVASCULAR COMPLICATIONS OF DIABETES MELLITUS DR.MONISHA MD(GENERAL MEDICINE)

2. MACROVASCULAR COMPICATIONS ARE Cardiovascular disease Cerebrovascular disease Peripheral Arterial disease

3. RISK FACTORS

4. HYPERGLYCEMIA INDUCED DAMAGE -increased polyol flux pathway -production of advanced glycation end products( glyoxal,methylglyoxal,deoxyglucosane formed from dicarbonyl precursors).
-increased hexosamine pathway
-increased protein kinase C activation
The root cause of all this is due to increased superoxide radicals because of hyperglycemia and excess fatty acid oxidation in insulin resistance
These ROS cause DNA breaks .PARP repairs it .
NAD+ broken down by PARP to NA and ADR
Polymers of ADR formed which inhibit glyceraldehyde 3 phosphate dehydrogenase which increases all intermediates above this step

5. IN INSULIN RESISTANCE

6. PATHOGENESIS ADIPOCYTE INFLAMMATION & INSULIN RESISTANCE REDUCED NITRIC OXIDE AVAILABILITY ENHANCED ATHEROSCLEROSIS ENHANCED PLATELET ACTIVATION & COAGULATION Diabetes is artherothrombotic state & all aspects of atherosclerosis are accentuated in presence of diabetes.

7. ADIPOCYTE INFLAMMATION & INSULIN RESISTANCE Adipocyte is an endocrine organ with capacity to influence insulince resistance ,inflammatory response & thrombosis. Free fatty acid activation of macrophage Interaction between resident macrophage & adipocyte Fat filled adipocytes

8. Increased amount of IL 6 , C 3 , TNF alpha , PAI – 1 Reduced adiponectin & increased leptin Insulin resistance

9. REDUCED NITRIC OXIDE BIOAVAILABILITY Hyperglycemia , hypertension , dyslipidemia , increased FFA , reduced adiponectin caused reduced nitric oxide production at transcriptional level. Nitric oxide stimulates vasodilatation by guanyl cyclase Reduced nitric oxide increased NF kappa B leucocyte adhesion molecule , chemokines , cytokines monocytes , vascular smooth cell migration. Diabetes increases vascular reactive oxygen species

10. Nitric oxide causes reduced adhesion of platelets to endothelium Diabetes causes platelet dysfunction & much of morbidity & mortality of diabetes is related to this thrombotic complication.

11. ENHANCED ATHEROSCLEROSIS

12. Diabetes – increases E selectin , VCAM 1 , ICAM 1 by endothelium. Up regulation of monotype chemoattractant Protein 1. Infiltrated macrophages elaborate cytokines , growth factors , MMP Promotes plaque expansion and plaque prone to thrombosis & rupture.

13. ENHANCED PLATELET ACTIVATION Increased PAI – 1 binds to tissue plasminogen activator Inhibit tPA induced plasmid generation Venous thrombosis & myocardial infarction

14. Hyperglycemia causes glycation on fibrinogen Dense structure with thin fibres of fibrin clot Increased cardiovascular risk

15. CORONARY ARTERY DISEASE Studies observe the hazard ratio of cardiovascular mortality risk in patients with diabetes is similar to that in non diabetic patients with MI Diagnosis of diabetes itself is a risk equivalent to prior MI

16. Proteinuria is a marker of generalized vascular damage that predispose to atherosclerosis. Therefore persistent proteinuria is a strong predictor of coronary artery disease. In patients with T2 DM higher LDL , lower HDL , higher HbA1c levels , systolic BP measurements & history of smoking - associated with risk of cardiovascular disease.

17. Pre diabetes refers to presence of impaired fasting glucose >100mg/dl & < 120mg/dl Impaired glucose tolarence defined as two hour post 75gm oral glucose load value of 140 – 199 mg/dl with fasting level <100mg/dl & HbA1c between 5.7 % - 6.7 % Impaired glucose tolerance – a pre diabetic state associated with insulin resistance is also risk factor for mortality. Hazard ratio for cardiovascular mortality increased as a linear function of two hour blood glucose for all values > 83mg/dl .

18. Screening for coronary artery disease in Diabetics Resting ECG Exercise ECG Stress myocardial perfusion imaging Stress ecocardiography Computed tomography Cardiac magnetic resonance imaging Catheterization and angiography

19. LIFESTYLE MANAGEMENT Weight reduction Medical nutritional therapy Physical activity Blood pressure Tobacco Antiplatelet drugs Glycemic control

20. CARDIOVASCULAR DISEASE WITH METABOLIC SYNDROME Metabolic syndrome based on presence of 3 of the following : Abdominal obesity ( waist circumference > 40 inches in men ; > 35 inches in women Plama triglyceride > 150mg/dl HDL <40 mg in mem < 50 mg in women Blood pressure 130/80 mmhg or higher Fasting blood glucose > 110mg/ dl or higher.

21. Cardiovascular mortality increased 2-3 fold in patient with metabolic syndrome. Each percentage point elevation in HbA1c increases cardiovascular risk by 11 %.

22. DYSLIPIDEMIA IN DIABETES

23. DYSLIPIDEMIA IN DIABETIC PATIENTS LLD particles in diabetes are smaller & dense triglyceride rich. More susceptible to oxidation In presence of poor glucose control. Increased glycation of LDL causes impaired recognition of lipoprotein by its hepatic receptors increasing its half life. Increased FFA Flux by insulin resistant adipocytes increases hepatic VLDL production.

24. Normally INSULIN & lipase mediate uptake of triglyceride derived FFA by striated muscle with reduced delivery to liver. In presence of lnsulin resistance this effect is reversed. According to ADA and American heart association in diabetic individuals without cardiovascular disease LDL <100mg/dl HDL >40mg/dl in men and >50 mg/dl in female Triglycerides <150g/dl With known cardiovascular risk LDL value of <70mg/dl recommended HMG COA REDUCTASE INHIBITORS statins have been incorporated in recent diabetes management guidelines which significantly reduces major coronary events and revascularisation in patients with diabetes Currently statins are accepted effective in reducing cerebrovascular accidents

25. PCSK9 GENE targets LDL receptor for proteosomal degradation rather then allowing it to return to the cell surface for another cycle of LDL Clearence .(EVOLOCUMAB,ALIROCUMAB) Fibric acid derivatives lower high triglycerides and raise HDL gemfibrozil had significant decrease in coronary events and strokes ACCORD trial showed combination therapy of statins and fibric acid would be more useful Niacin lack efficacy combined with its side effects of increasing insulin tolerance

26. HYPERTENSION IN DIABETICS Increased duration of diabetes causes increased arterial stiffness and reduced vasomotor function and loss of nocturnal Bp dip Target BP <130/80 mm hg with foremost emphasize on lifestyle modifications ADA recommends ACE inhibitors or ARBS with betablockers /thiazides/CCB In patients with type 1 diabetes, hypertension,micro and macroalbuminuria ACE inhibitors slowed progression of nephropathy In patients with type 2 it slowed Progression of macroalbiminuria and decline in GFR. Non hydropyridine calcium channel blockers preferred over dihydroyridine Agents in diabetics

27. ACUTE CORONARY SYNDROME IN DIABETICS Increased risk of heartfailure due to maladaptive remodeling of left ventricle Increased risk of sudden death due to sympathovagal inhibition as a consequence of autonomic neuropathy Increased early reinfarction due to impaired fibrinolysis Extensive underlying atherosclerosis Changes in myocardial cell metabolism by shift of glucose oxidation to free fatty acid oxidation with less ATP generation Associated cardiomyopathy

28. Intensive glycemic control improve myocardial cell metabolism and reverse the impaired fibrinolysis ACE inhibitors dramatically reduce infarction size and limit ventricular remodeling Beta blockers dampen the effect of sympathetic overactivity that arises as a consequence of autonomic neuropathy Aspirin cornerstone of primary and secondary prevention which modulates aggregation of platelets Antagonist of P2Y12 subclass – clopidogrel,prasugrel,ticagrelor reduce rate of ischemia in acute coronary syndrome

29. Glycoprotein IIb /III a( abciximab,eptifibatide,tirofiban ) antagonise platelet action.The rate of target vessel revascularisation significantly decreased with additional of this antagonist A study showed that CABG showed better outcomes than PTCA and reduced 5 year mortality

30. CARDIOMYOPATHY IN DIABETES

31. CARDIOMYOPATHY IN DIABETES MELLITUS Diabetes associated with fourfold increase in risk of CCF FACTORS CONTRIBUTING Diabetes induced cardiomyocyte dysfunction due to altered substrate utilisation Impaired microvascular perfusion because of defective endothelial function Increased collagen deposition with fibrosis due to increased activation of RAAS and formation of AGEs Maladaptive remodeling after MI

32. Evidence of silent myocardial infarction is found in 40 percent of patients with diabetes who present with clinically apparent infarct and unrecognized regional and global ventricular dysfunction On cellular level both hyperglycemia and insulin resistance depress myocardial GLUT4 levels as a result metabolism shifts from glycolysis to FFA oxidation thereby reducing ATP generation a major source during ischemic conditions The combination of ARB(valsartan) and a nephrilysin inhibitor( sacubitril )proved superior to ACE Inhibitor in patients with reduced ejection fraction

33. CEREBROVASCULAR DISEASE Strokes can be either is ischemic or hemorrhagic Ischemic strokes are classified as Large artery atherosclerosis Cardioembolism Lacunar strokes Other determined etiology Undetermined etiology Patients with diabetes are more prone for lacunar infarcts

34. Risk of ischemic stroke in diabetic patients is increased by 1.5-4 times Diabetics of more than 65 yrs have 12 fold increased risk than non diabetics 17 percent increase in risk of stroke with each 1% rise in HbA1C Risk factors for stroke in Diabetes Diabetic retinopathy Hyperuricemia Proteinuria >300mg/dl Concomitant hypertension

35. An elevated blood sugar can be seen in more than 40 percent of patients with ischemic stroke especially in diabetics Normally glucose metabolized to pyruvate In ischemic brain pyruvate to lactate accumulation of lactate and intracellular acidosis accumulation of intracellular calcium Glutamate dependent excitotoxicity and cell death

36. The current standard of care of patients with acute ischemic stroke is thrombolysis with iv recombinant tissue plasminogen activator Hyperglycemia is one of the important risk factor for developing subsequent ICH In acute ischemic stroke blood sugar maintained below 180 mg/dl with insulin.High blood glucose will impair brain plasticity and functional recovery